Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL.
J Cell Biol. 2021 Sep 6;220(9). doi: 10.1083/jcb.202005193. Epub 2021 Jul 14.
Long-lived proteins (LLPs) have recently emerged as vital components of intracellular structures whose function is coupled to long-term stability. Mitochondria are multifaceted organelles, and their function hinges on efficient proteome renewal and replacement. Here, using metabolic stable isotope labeling of mice combined with mass spectrometry (MS)-based proteomic analysis, we demonstrate remarkable longevity for a subset of the mitochondrial proteome. We discovered that mitochondrial LLPs (mt-LLPs) can persist for months in tissues harboring long-lived cells, such as brain and heart. Our analysis revealed enrichment of mt-LLPs within the inner mitochondrial membrane, specifically in the cristae subcompartment, and demonstrates that the mitochondrial proteome is not turned over in bulk. Pioneering cross-linking experiments revealed that mt-LLPs are spatially restricted and copreserved within protein OXPHOS complexes, with limited subunit exchange throughout their lifetimes. This study provides an explanation for the exceptional mitochondrial protein lifetimes and supports the concept that LLPs provide key structural stability to multiple large and dynamic intracellular structures.
长寿命蛋白（LLPs）最近成为细胞内结构的重要组成部分，其功能与长期稳定性相关。线粒体是多功能细胞器，其功能依赖于蛋白质组的有效更新和替换。在这里，我们使用代谢稳定同位素标记的小鼠结合基于质谱（MS）的蛋白质组学分析，证明了一部分线粒体蛋白质组具有显著的长寿特性。我们发现，线粒体长寿命蛋白（mt-LLPs）可以在长期存在的细胞（如大脑和心脏）的组织中持续数月。我们的分析表明，mt-LLPs 在内膜内富集，特别是在嵴亚区，并表明线粒体蛋白质组不是整体被替换的。开创性的交联实验表明，mt-LLPs 在空间上受到限制，并在整个寿命过程中在 OXPHOS 复合物内保持共保存，其亚基交换有限。这项研究为异常的线粒体蛋白质寿命提供了一个解释，并支持 LLP 为多个大型和动态的细胞内结构提供关键结构稳定性的概念。
